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Bearing-resisting compound and preparing method

An anti-fertility and compound technology, applied in the field of medicine, can solve the problems of poor solubility of 4-guanidinobenzoic acid hydrochloride, no anti-fertility preparations, long reaction time, etc., so as to improve the anti-fertility effect and shorten the reaction time. , the effect of simple reaction

Inactive Publication Date: 2003-08-27
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] 1. Steps (1) to (3), the reaction time is long, the operation is cumbersome, and the total yield is low;
[0012] 2, use methyl iodide in step (2), the price is more expensive;
[0013] 3. The anhydrous requirement of step (5) is high, the post-treatment is cumbersome, and the yield is extremely low, especially the esterification reaction of 4-guanidinobenzoic acid hydrochloride and methyl p-hydroxybenzoate, and the method of dehydrating esterification with DCC , the reaction is not complete, the post-processing is difficult, and the yield is very low
[0014] Due to the above-mentioned deficiencies, and the poor solubility of 4-guanidinobenzoic acid (4-methoxyformyl) phenyl ester hydrochloride, so although it has the report of inhibiting acrosinase activity, it has not been seen so far to prepare antifertility preparations with this compound report

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: the preparation of 4-guanidinobenzoic acid hydrochloride (III)

[0035] 13.7g (0.10mol) of 4-aminobenzoic acid, 20.12g (0.10mol) of 1-amidino-3,5-dimethylpyrazole nitrate in 200ml ethanol, magnetically stirred, refluxed for 8 hours under nitrogen protection, and recovered Ethanol, add 10% sodium hydroxide solution to the residue to pH 9, add 2 g of activated carbon to decolorize, add 10% hydrochloric acid to the filtrate to neutralize to pH 3, and precipitate a solid. Add distilled water to boil the solid to dissolve, let it cool, and slowly precipitate a needle-shaped colorless solid, and filter it with suction to obtain 15.7 g of 4-guanidinobenzoic acid hydrochloride as a white solid, with a yield of 72.7%. mp: 276-277°C.

[0036] The nuclear magnetic resonance instrument records its proton nuclear magnetic resonance spectrum as follows:

[0037] 1 HNMRδ (DMSO, 300MHz): 7.19 (2H, d, J = 4.86); 7.94 (2H, d, J = 4.84); 8.33 (4H, s); 12.18 (1H, s)

Embodiment 2

[0038] Embodiment 2: the preparation of 4-guanidinobenzoic acid (4-methoxyformyl) phenyl ester hydrochloride (V)

[0039] 23.3g (0.10mol) of 4-guanidinobenzoic acid hydrochloride (III), 119g (1.00mol) of thionyl chloride, magnetically stirred, refluxed for 1.5 hours, let cool, added 100ml of petroleum ether, filtered to obtain 4-guanidine Benzoyl chloride hydrochloride.

[0040] Add 15.2 g (0.10 mol) of methyl 4-hydroxybenzoate (IV), 150 ml of anhydrous tetrahydrofuran, and 10.1 g (0.10 mol) of triethylamine to another reaction flask, and stir the reaction, maintaining the temperature at 3 to 2 ° C to rapidly Add the above-mentioned 4-guanidinobenzoyl chloride hydrochloride, react in an ice bath for 2 hours, stir at room temperature for 3 hours, filter, filter cake is fully washed in four times with 160 ml of ether, drained, and dried to obtain 4-guanidinobenzoic acid ( 4-methoxyformyl)phenyl ester hydrochloride (V) white solid 32g°C yield 91.5%, melting point 255-257°C.

Embodiment 3

[0041] Embodiment 3: the preparation of 4-guanidinobenzoic acid (4-methoxyformyl) phenyl ester methanesulfonate (VI)

[0042] 4-Guanidinobenzoic acid (4-methoxyformyl) phenyl ester hydrochloride (V) 32g, dimethyl sulfoxide 150ml, stir to dissolve; 0.10mol sodium hydroxide 40ml is dropped into dimethyl sulfoxide solution under ice bath , stirred in an ice bath for 1 hour, poured the reaction solution into ice-distilled water; extracted 3 times with ethyl acetate, combined the ethyl acetate solution, added 9.6 g (0.10 mol) of methanesulfonic acid, concentrated to remove an appropriate amount of ethyl acetate solution, Solids filtered. Recrystallization from absolute ethanol gave 18 g of pure 4-guanidinobenzoic acid (4-methoxyformyl)phenyl methanesulfonate (VI), with a yield of 48.1%. The melting point is 215-217°C.

[0043] The nuclear magnetic resonance instrument records its proton nuclear magnetic resonance spectrum as follows:

[0044] 1 HNMR (DMSO, 300MHz): 3.88(3H, s);...

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Abstract

The invention refers to anti-procreative compound 4-guanidino benzoic acid (4-carbomethoxy) phenyl ester methane sulfonate and the making method as well as anti-procreative preparation made from it. The compound has the activity to restrain the acrosome enzyme, its solubility small, the making method complex and the rate of preparation low.

Description

Technical field: [0001] The invention relates to the technical field of medicine, and relates to an anti-fertility compound 4-guanidinobenzoic acid (4-methoxyformyl) phenyl ester methanesulfonate, a preparation method thereof and an anti-fertility preparation prepared by the same. Background technique: [0002] Human sperm acrosome protease is an essential proteolytic enzyme in the fertilization process, and acrosome protease inhibitors can inhibit the activity of sperm acrosome protease, affect the acrosome reaction of sperm and the ability to penetrate eggs, so as to achieve the contraceptive effect. It is reported that 4-guanidinobenzoic acid (4-methoxyformyl) phenyl ester hydrochloride has inhibitory acrosome activity (see J.Med.Chem.1986,29,514~519 for details), and the chemical structural formula is: Its classic preparation route is as follows: [0003] The reaction steps are: [0004] (1) p-aminobenzoic acid reacts with ammonium thiocyanate in the presence of h...

Claims

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Application Information

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IPC IPC(8): A61K31/255A61P15/18C07C303/32C07C309/04
Inventor 吕加国赵亚南周有骏朱驹纪亚忠张万年崔英惠宁季海涛余建鑫刘玉环宋云龙盛春泉章玲张俊洁徐明娟许翠琴王贺玲
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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